Behavioural Brain Research 73 ( 1996) 121-124 SSSSSSSS
Human psychopharmacology of N,N-dimethyltryptamine
Rick J. Strassman*
Department of Psychiatry, University of New Mexico, Albuquerque, NM 87131-5326 USA
We generated dose-response data for the endogenous and ultra-short-acting hallucinogen, N,N-dimethyltryptamine (DMT), in
a cohort of experienced hallucinogen users, measuring multiple biological and psychological outcome measures. Subjective
responses were quantified with a new rating scale, the HRS, which provided better resolution of dose effects than did the biological
A tolerance study then was performed, in which volunteers received four closely spaced hallucinogenic doses of DMT. Subjective
responses demonstrated no tolerance, while biological measures were inconsistently reduced over the course of the sessions. Thus,
DMT remains unique among classic hallucinogens in its inability to induce tolerance to its psychological effects.
To assess the role of the 5-KT 1A site in mediating DMT's effects, a pindolol pre-treatment study was performed. Pindolol
significantly increased psychological responses to DMT, suggesting a buffering effect of 5-HT lj4 agonism on 5-HT 2 -mediated
psychedelic effects. These data are opposite to those described in lower animal models of hallucinogens' mechanisms of action.
Human research with hallucinogenic drugs was
severely curtailed by the passage of the Controlled
Substances Act of 1970 . Nearly a generation
elapsed before a renewal of clinical studies occurred in
the United States and Europe. These studies have begun
to address gaps in basic understanding of effects and
mechanisms of action created by this hiatus, during
which many of the standard methods of psychopharma-
cology and psychotherapy research were developed.
There are several reasons why the careful study of
hallucinogens has relevance to psychiatric research.
(1) The clinical syndrome elicited by hallucinogens
affects all of the mental functions associated with human
consciousness, including mood, perception, cognition,
self-control and somatic awareness . Generating
mechanistic hypotheses based upon systematic data col-
lection will provide insights into many basic brain-mind
(2) Use and abuse of hallucinogens among young
adults is increasing [10,11], with an attendant rise in
emergency room and psychiatric clinic utilization for
assessment and treatment of adverse effects . There
is a need to understand how best to treat hallucinogen-
elicited psychiatric disorders quickly, safely, and effec-
* Corresponding author.
tively, in addition to providing accurate information to
clinicians regarding effects and sequelae of hallucinogen
use and abuse.
(3) The degree of overlap between endogenous psycho-
ses and hallucinogenic drug inebriation has been debated
vigorously [8,12]. The appellations 'psychotogen' and
'psychotomimetic' bespeak early efforts to relate the two
syndromes. Similarities appear to be greatest during
acute phases of schizophrenia . Short-chain tryptam-
ines remain attractive candidates for naturally occurring
psychotogens . Current interest in mixed 5-HT 2 /DA 2
antagonists as anti-psychotic agents  also under-
scores the importance of studying 5-HT 2 -active halluci-
nogens as models for endogenous psychoses.
(4) The ability of hallucinogens to enhance the psy-
chotherapeutic process was an area of intense interest
during the first phase of hallucinogen research .
Restrictions on human use of these drugs prevented
necessary clarification regarding with whom, and how
best to utilize these drugs within a psychotherapeutic
context. Recent advances in psychotherapy research 
suggest models by which a more careful and systematic
approach to combining hallucinogen drug administra-
tion with well-characterized forms of psychotherapy
We have been investigating effects and mechanisms
of action of the short-chain tryptamine, ultra-short-
acting endogenous hallucinogen, N,N-dimethyltrypta-
0166^328/96/59.50 © Elsevier Science B.V. All rights reserved
Rick J. Strassman/ Behavioural Brain Research 73 ( 1996) 121-124
mine (DMT), in a cohort of experienced hallucinogen
users since November, 1990. Three reasons prompted
choosing DMT as the compound with which to renew
clinical research with hallucinogens. First, it is extremely
short-acting , and adverse effects which might occur
in a busy clinical research unit would be easier to
manage. Second, it is a naturally occurring hallucinogen
[ 1 ], whose role in normal and abnormal mental processes
has yet to be explicated adequately. Third, its relative
obscurity would not draw undue attention to our work
in the early delicate stages of resuming this research,
relative to the certain flurry of interest that a better
known hallucinogen, such as LSD, might.
We chose to study experienced hallucinogen users for
the following reasons: experienced users would be less
likely to panic during the powerful hallucinogenic effects
expected from DMT; they would be able to provide
more detailed accounts of DMT effects, particularly
relative to other better known compounds, such as LSD
and psilocybin, than naive subjects; finally, liability for
development of subsequent 'drug abuse' would be less
likely to be sustained in previous or current users.
2. Summary of experiments and results
Each of the three studies to be described utilized
male and female experienced hallucinogen users who
were otherwise medically and psychiatrically healthy.
Screening was rigorous, and included a medical history,
physical examination, electrocardiogram, urinalysis,
complete blood count, 24-item chemistry panel, and
thyroid functions. Subjects were excluded who were
taking any medication regularly, or who had a history
of high blood pressure. Psychiatric screening included a
semi-structured psychiatric interview, the Structured
Clinical Interview for DSM-III-R, Outpatient , and
a survey of drug use history. Those with current drug
abuse problems or history of psychosis were excluded.
If volunteers had a history of a major depressive episode,
they were included if the depression had resolved at
least two years before beginning the study, and they
were not in stressful life circumstances conducive to a
relapse. In addition, if volunteers had not had what the
research team considered 'full-blown' experiences on
hallucinogenic drugs, they were not enrolled, as we
wanted to ensure that volunteers could manage the
highly intoxicated state of a high-dose DMT session.
Studies all took place in the inpatient unit of the
University of New Mexico Hospital Clinical Research
Center. Prospective volunteers first received low
(0.05 mg/kg) and high (0.4 mg/kg) screening doses of
intravenous (i.v.) DMT fumarate, non-blind, to familiar-
ize themselves with the research setting, provide an
opportunity to drop out before extensive data were
collected, and for idiosyncratic hypertensive responses
to the low dose to be noted and exclude further
Our first dose-response study utilized 0.05, 0.1, 0.2
and 0.4 mg/kg i.v. DMT fumarate, and saline placebo,
in a double-blind, randomized design, using 12 volun-
teers. These results have been published [22,23]. A new
rating scale for hallucinogen effects, the Hallucinogen
Rating Scale (HRS), was developed, which clustered
responses into six clinical categories: Affect, Volition,
Somatic Effects ('Somaesthesia'), Perception, Cognition,
and Intensity. Biological measures included: heart rate
(HR), mean arterial blood pressure (MAP), pupil diame-
ter, core temperature; and adrenocorticotropin (ACTH),
/i-endorphin (/?E), prolactin (PRL), growth hormone
(GH), melatonin, Cortisol and DMT-free base blood
levels. The 'psychedelic' threshold for DMT was at
0.2 mg/kg, at which most biological effects also demon-
strated statistically significant differences from saline
placebo. Only melatonin showed no stimulation by
DMT, while GH levels, although stimulated, could not
be differentiated by dose. Pupil diameter, HR, MAP,
ACTH, /?E, DMT, and subjective responses all peaked
within 2 min; PRL and Cortisol responses lagged by
5-15 min, while temperature and growth hormone eleva-
tions did not begin until psychological effects had
resolved, by 15-20 min.
Psychological effects began nearly immediately during
the DMT infusion, peaked within 2 min, and usually
were completely resolved within 30 min. The higher
doses of DMT produced a rapidly moving, multi-dimen-
sional, kaleidoscopic display of intensely colored abstract
and representational images. Auditory effects were less
common, and were not frank hallucinations. Transient
anxiety was common, but usually quickly became
replaced by euphoria. Dissociation of awareness from
the physical body was common, as were later feelings of
alternating heat and cold. The higher dose effects com-
pletely replaced ongoing mental experience, and usually
was described as more compelling and convincing than
'ordinary' reality or dreams. Lower doses (0.1 and
0.05 mg/kg) primarily affected physical and affective
functions, with little perceptual disturbances. HRS data
were more capable of distinguishing between dose levels
(e.g., between 0.1 and 0.05 mg/kg) than were biological
data. These data were interpreted in the light of
5-HT mechanisms, especially 5-HT 2 and 5-HT lx site
More experimental studies were then designed, the
first being an assessment of DMT's ability to induce
tolerance to its biological and psychological effects.
Previous attempts in humans had failed to elicit toler-
ance , while heroic efforts in lower animals were
required to do so .
A fully hallucinogenic dose, 0.3 mg/kg, of i.v. DMT
fumarate, or saline placebo, was administered at half-
hour intervals, 4 times in a morning, to 1 3 experienced
Rick J. Strassman/ Behavioural Brain Research 73 (1996) 121-124
hallucinogen-using volunteers. Neither clinical inter-
views nor HRS results demonstrated development of
psychological tolerance. HR decreased from the first to
second session, and did not change thereafter, suggesting
'reduction of anticipatory anxiety,' rather than 'toler-
ance;' while no reduction in MAP was seen. ACTH and
PRL responses did decrease over the course of the
morning, suggesting tolerance development. This
differential tolerance development was interpreted as
being mediated by independently regulated desensitiza-
tion of relevant 5-HT receptor mechanisms. Thus, DMT
remains unique in its inability to develop tolerance to
its psychological effects.
Our last study completed assessed the role of the
5-HT 1j4 site in mediating DMT effects. This was per-
formed because DMT has nearly equal affinity for the
5-HT 1A and 5-HT 2 sites , and the behavioral effects
of the hallucinogen 5-methoxy-DMT are blocked by
pindolol , a potent 5-HT lA antagonist .
Twelve volunteers received a sub-hallucinogenic dose,
0. 1 mg/kg, i.v. DMT, or saline placebo, in combination
with 30 mg oral racemic pindolol, or placebo-pindolol,
in a four-cell double-blind, randomized design.
Volunteers found that pindolol pre-treatment enhanced
DMT effects by two to three times, which was substanti-
ated by scores on the HRS, in which four to six clinical
clusters demonstrated a significant enhancement by pin-
dolol. PRL responses were reduced, while those of
ACTH were unaffected. HR responses were blunted,
probably due to pindolol's anti-sympathetic effects,
while MAP effects were enhanced. These behavioral
data, opposite to those noted in the animal literature,
suggest an inhibitory effect of 5-HT M agonism in tryp-
tamine-induced hallucinogenesis. Pindolol blockade
allowed unopposed 5-HT 2 agonism, which we believe
also mediated the enhanced MAP responses to DMT.
The reduced PRL response supports a stimulatory role
for the 5-WY lA site in human PRL secretion, while the
lack of effect on ACTH suggests a minimal role for this
site in the DMT response. These data also are important
because they demonstrate differential (and at times,
opposite) regulation of neuroendocrine, cardiovascular,
and subjective effects of hallucinogens in humans.
3. Conclusions and future directions
DMT can be safely administered to experienced hallu-
cinogen users in fully 'psychedelic' doses. By so doing,
earlier clinical research findings can be extended to
include contemporary psychopharmacological method-
ologies, and basic hypotheses tested. In the case of DMT,
a battery of neuroendocrine data have been generated,
and a new rating scale developed. The lack of tolerance
to DMT's psychological effects has been established
more rigorously, which strengthens its role as a putative
endogenous 'psychotogen' . Our study of the role of
the 5-HT 1A site in mediating DMT effects in humans
has yielded results opposite to those expected from
Current studies include a pre-treatment protocol using
the only currently available 5-HT 2 antagonist, cyprohep-
tadine, which will expand previous human work with
this combination . In addition, we are beginning to
develop comprehensive dose-response data for the
longer-acting, and more widely abused hallucinogen,
psilocybin ( 4-phosphoryloxy-N,N-DMT ) .
This investigation was supported by the Scottish Rite
Foundation for Schizophrenia Research, NMJ; National
Institute on Drug Abuse grants RO3-DA06524 and
RO1-DA08096; University of New Mexico General
Clinical Research Center grant RR00997; the Scott
Rogers Fund of the University of New Mexico; and
University of New Mexico Department of Psychiatry
research funds. The authors would like to thank David
E. Nichols, Ph.D., Purdue University, for synthesis of
the DMT fumarate used in this study.
[ 1 ] Axelrod, J., The enzymatic N-methylation of serotonin and other
amines, J. Pharmacol. Exp. Ther., 138 ( 1962) 28-33.
 Bowers, M., Jr. and Freedman, D.X., 'Psychedelic' experiences in
acute psychoses, Arch. Gen. Psychiatry, 15 (1966) 240-248.
 Corbett, L., Christian, S.T., Morin, R.D., Benington, F. and Smy-
thies, J.R., Hallucinogenic N-methylated indolealkylamines in the
cerebrospinal fluid of psychiatric and control populations, Br.
J. Psychiatry, 132 (1978) 139-144.
 Deliganis, A.V., Pierce, P.A. and Peroutka, S.J., Differential inter-
actions of dimethyltryptamine (DMT) with 5-HT lj4 and 5-HT 2
receptors, Biochem. Pharmacol., 41 (1991) 1739-1744.
 Freedman, D.X., On the use and abuse of LSD, Arch. Gen. Psychi-
atry, 18 (1968) 330-347.
 Gillin, J.C., Kaplan, J., Stillman, R. and Wyatt, R.J., The
psychedelic model of schizophrenia: The case of N,N-dimethyl-
tryptamine, Am. J. Psychiatry, 133 (1976) 203-208.
 Gold, M.S., Schuchard, K. and Gleaton, T., LSD use among US
high school students (letter), JAMA, 271 (1994) 426-427.
 Hollister, L., Drug-induced psychoses and schizophrenic reac-
tions: A critical comparison, Ann. N.Y. Acad. Set, 96 (1962)
 Hollister, L.E., Some general thoughts about endogenous psy-
chotogens. In E. Usdin, D.A. Hamburg and J.D. Barchas (Eds.),
Neuroregulators and Psychiatric Disorders, Oxford University
Press, New York, 1977, pp. 550-556.
 Johnston, L.D., O'Malley, P.M. and Bachman, J.G., National
Survey Results on Drug Use from Monitoring the Future Study,
1975-1992, Vol. II. College Students and Young Adults, National
Institute on Drug Abuse, Rockville, MD, 1993.
[ 1 1 ] Johnston, L.D., O'Malley, P.M. and Bachman, J.G., National
Survey Results on Drugs Use from Monitoring the Future Study,
Rick J. Strassman/ Behavioural Brain Research 73 ( 1996) 121-124
1975-1992, Vol. I. Secondary School Students, National Institute
on Drug Abuse, Rockville, MD, 1993, 269 pp.
 Kleinman, J.E., Gillin, J.C. and Wyatt, R.J., A comparison of the
phenomenology of hallucinogens and schizophrenia from some
biographical accounts, Schizophr. Bull, 3 (1977) 560-586.
 Kovacic, B. and Domino, E.F., Tolerance and limited cross-
tolerance to the effects of N,N-dimethyltryptamine (DMT) and
lysergic acid diethylamide-25 (LSD) on food-rewarded bar
pressing in the rat, J. Pharmacol. Exp. Ther., 197 ( 1976) 495-502.
 Meltzer, H.Y., Clinical studies on the mechanism of action of
clozapine: the dopamine-serotonin hypothesis of schizophrenia,
Psychopharmacology, 99 (1989) S18-S27.
 Meltzer, H.Y., Wiita, B., Tricou, B.J., Simonovic, M„ Fang, V.S.
and Manov, G., Effects of serotonin precursors and serotonin
agonists on plasma hormone levels. In B.T. Ho. J.C. Schoolar
and E. Usdin (Eds.), Serotonin in Biological Psychiatry, Raven,
New York, 1982, pp. 117-139.
 Oksenberg, D. and Peroutka, S.J., Antagonism of
5-hydroxytryptamine lyl (5-HT ly) ) receptor-mediated modulation
of adenylate cyclase activity by pindolol and propranolol isomers.
Biochem. Pharmacol, 37 (1988) 3429-3433.
 Pahnke, W.N., Kurland, A.A., Unger, S., Savage, C. and Grof.
S., The experimental use of psychedelic (LSD) psychotherapy.
JAMA, 212 (1970) 1856-1863.
 Sai-Halasz, A., Brunecker, G. and Szara, S.I., Dimethyltryptamin:
ein neues Psychoticum, Psychiat. Neurol, Basel, 135 (1958)
 Spencer, D., Jr., Glaser, T. and Traber, J., Serotonin receptor
subtype mediation of the interoceptive discriminative stimuli
induced by 5-methoxy-N,N-dimethyltryptamine, Psychopharma-
cology, 93 (1987) 158-166.
 Spitzer, R., Williams, J. and Gibbon, M., Structured clinical inter-
view for DSM-1II-R — Outpatient version, Biometric Research
Department, New York State Psychiatric Institute, New York,
[21 ] Strassman, R.J., Human hallucinogenic drug research in the
United States: a present-day case history and review of the pro-
cess, J. Psychoactive Drug, 23 (1991) 29-38.
 Strassman, R.J. and Quails, C.R., Dose-response study of N,N-
dimethyltryptamine in humans, I. Neuroendocrine, autonomic,
and cardiovascular effects, Arch. Gen. Psychiatry, 51 (1994)
 Strassman, R.J., Quails, C.R., Uhlenhuth, E.H. and Kellner, R.,
Dose-response study of N,N-dimethyltryptamine in humans, II.
Subjective effects and preliminary results of a new rating scale,
Arch. Gen. Psychiatry, 51 (1994) 98-108.
 Weissman, M.M. and Markowitz, J.C, Interpersonal psycho-
therapy, Arch. Gen. Psychiatry, 51 (1994) 599-606.